Obstructive sleep apnea (OSA) is a serious, potentially life-threatening highly prevalent chronic disorder. It is an important and unresolved public health care problem because of its role in the development of cardiovascular events, negative impact on quality of life, and as a cause of traffic accidents. The signs, symptoms and consequences of OSA are direct results of repetitive episodes of airflow cessation (i.e., apnea) or reduction (i.e., hypopnea) due to repetitive collapse of the upper airway. Reduced ventilation during sleep causes repetitive episodes of hypoxemia, increased arterial CO2, and decreased arterial O2. A correlation has been clearly established that patients with OSA are often associated with cardiovascular diseases (e.g., systemic hypertension, pulmonary hypertension, arrhythmia, and heart failure), neuropsychiatric diseases (e.g., cognitive dysfunction caused by excessive daytime sleepiness, lowered quality of life caused by snoring, fragmented sleep due to arousals, and depression), and metabolic diseases (e.g., obesity, diabetes mellitus, and insulin resistance). OSA affects at least 2% to 4% of the adult population and is increasingly recognized by the public. A more recent report estimates that OSA affects approximately 5% of adults; however, the prevalence of OSA may be increasing because of recent obesity trends.
Continuous positive airway pressure (CPAP) is currently the first-line standard of care for treating OSA. By delivering a fan generated airflow, CPAP maintains airway patency by creating a “pneumatic splint.” In most patients, CPAP dramatically reduces or eliminates apnea and hypopnea episodes. However, the effectiveness of CPAP depends directly on patients' utilization of the machine and mask. Only half of those individuals who accept CPAP are still using it at the end of one year, and even fewer use it to the extent prescribed. Surgical treatment has also been used to treat OSA, and surgical techniques include stage I surgery (e.g., nasal surgery, uvulopalatopharyngoplasty, and base of tongue surgery) and stage II surgery (e.g., maxillomandibular advancement). The goal of surgery is to provide site-specific treatment to increase airway size and decrease airway resistance, thereby reducing work of breathing. A successful site-specific airway reconstruction often depends on the site of obstruction which is unique to each patient and is not consistent within patients. These mechanical and surgical treatments are inconvenient and often intrusive to patients.
Various pharmaceutical agents have been trialed for the treatment for OSA, but none has been found to be adequately effective. Hedner and Kraiczi initially claimed treatment of snoring, sleep apnea and other forms of sleep-disordered breathing with an acetylcholinesterase inhibitor (CEI) based on a clinical study of patients with moderate to severe OSA treated with continuous intravenous infusion of physostigmine salicylate at 12 μg/min/kg for a period of 7 hours, and provided a list of other CEIs, including pyridostigmine, particularly useful for the treatment (U.S. Pat. No. 6,034,117). After publishing subsequent reports on similar results in patients treated with continuous intravenous infusion of physostigmine at 0.12 μg/min/kg for a period of 7 hours or donepezil, Hedner disclosed that more recent unpublished data did not fully support the initial promising findings and concluded that the therapeutic potential of CEIs in OSA remained to be clarified (Hedner et al. (2008), Sleep Medicine Reviews 12:33-47).
Therefore, there remains a need for a convenient, less intrusive and effective OSA treatment, especially a potent therapeutic agent that can be easily administered.